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Pulmonary Surfactant Protein-A (SP-A) Reduces Adverse Outcomes In a Rat Pup Model of Necrotizing Entercolitis (NEC)

Saturday, October 20, 2012: 9:40 AM
Room 353-355 (Morial Convention Center)
Hector Quintanilla, MD1, Joseph Alcorn, PHD1, J. Marc Rhoads, MD2, Yuying LIU, PHD2, Nicole Fatheree2, Constance Atkins, BS1 and Weizhen Bi, BS1, (1)Department of Pediatrics, Neonatal-Perinatal Medicine, University of Texas Medical Center at Houston, Houston, TX, (2)Department of Pediatrics, Department of Pediatric Gastroenterology and Nutrition, University of Texas Medical Center at Houston, Houston, TX

Purpose

While necrotizing enterocolitis (NEC) is one of the leading causes of morbidity and mortality in premature infants, its etiology is incompletely understood and specific treatment strategies are lacking.  It is thought that NEC arises from ischemic injury of the immature gut, but enteric feeding, abnormal bacterial colonization, inflammation, toll-like receptor activation and damage from free radicals in the gut play major roles.  The expression and activity of pulmonary surfactant protein A (SP-A), a protein central to innate immunity of the lung, has been shown to impact or be impacted by many of these same factors. Others have reported that SP-A null mouse pups raised in a non-sterile environment had significant mortality that was associated with considerable gastrointestinal tract pathology resembling NEC, but no lung pathology.  Furthermore, purified human SP-A delivered by mouth to the pups improved survival.  In light of these findings and the fact that SP-A is expressed in the gut, we hypothesized that SP-A could play a role in the development of NEC.  

Methods

NEC was induced in newborn Sprauge-Dawley rat pups by formula gavage and intermittent episodes of hypoxic stress over 4 days. In this study, newborn pups were gavaged daily with formula with (FS) and without (F) 5 µg of purified SP-A.  NEC was induced in the pups by 10 min of hypoxia (H)(5% O2) thrice daily. Surviving pups were sacrificed distal 2 cm of terminal ileum was harvested for morphological studies, analysis of cytokine levels and SP-A expression.  

Results

Survival was 65% in the hypoxic pups (FH), while survival was 95% in the hypoxia pups treated with SP-A (FHS), indicating a protective effect of SP-A.  NEC was assessed by histological examination of ileal sections and a 4 point (0-3) scoring system based on severity where scores ≥2 are defined as having developed NEC.  28% of the F pups had histological NEC while 18% of the FS pups were assessed to have NEC.  As expected, a majority (61%) of the FH pups had NEC, while SP-A administration significantly reduced NEC in hypoxia-treated pups (FHS) (15%), P(FH vs FHS) = 0.021, as determined by chi square analysis. 

Conclusions

Expression of SP-A in the lung and gut was not significantly changed by SP-A treatment.  Induction of NEC increased interleukin-4 (IL-4), IL-5 and interferon- levels in the gut (determined by ELISA). These cytokines were reduced 2-fold by the presence of SP-A.  These results suggest that while NEC does not alter endogenous SP-A levels in the gut or lung, exogenous SP-A significantly reduces histological assessment of NEC in this model and favorably alters the cytokine milieu of the gut.